BASOPHIL PRIMING BY NEUROTROPHIC FACTORS - ACTIVATION THROUGH THE TRKRECEPTOR

There is increasing evidence that nerve growth factor (NGF) acts on ce lls of the immune system, apart from its neurotrophic effects. In huma n basophils, NGF potentiates mediator release and primes the cells to produce leukotriene C-4 in response to C5a. It is, however, unknown wh ether other homologous neurotrophins also act outside the nervous syst em, and whether activation of basophils by NGF requires interaction wi th trk tyrosine kinase receptors, the low affinity NGF receptor (LNGFR ), or both. A triple mutant NGF designed to interrupt binding to the L NGFR was found to activate basophils with equal efficacy as wild-type NGF, demonstrating that the LNGFR is not necessary. Despite a 10 times lower potency of mutant NGF, no LNGFR expression was detected by FAGS analysis. Brain-derived neurotrophic factor, which interacts with trk B, was inactive at concentrations up to 1000 ng/ml (>30,000-fold lower potency than NGF), while neurotrophin-3, which is thought to interact with trkC, trkB, and more weakly with trk, induced a threshold effect at 300 ng/ml (similar to 10,000-fold lower potency), demonstrating th at 1) the LNGFR cannot deliver a direct signal; and 2) basophils do no t express functional trkB and trkC receptors. In agreement with the fu nctional data, basophils (in contrast to other granulocyte types) expr essed mRNA for trk, but not trkB or trkC, and no or minimal mRNA for L NGFR. These data demonstrate that human blood basophils express functi onal trk receptors that do not require the participation of LNGFR, and that, among the neurotrophin family, NGF is unique in priming basophi ls.